Hydroxy-oligocarboxylic esters: effects on nerve and use for cutaneous and mucocutaneous organs or sites

ABSTRACT

A composition and method for producing a beneficial effect on a subject&#39;s nerve associated with at least one of a cosmetic condition, a dermatological indication and a dental indication and another condition. The composition comprises a hydroxy-oligocarboxylic ester and is formulated for topical administration of the product to a subject to produce the beneficial effect. The method includes topically applying to the subject in a region where the beneficial effect is desired a hydroxy-oligocarboxylic ester in an amount effective to produce the beneficial effect.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 11/548,945 filed on Oct. 12, 2006, which claims the benefitunder 35 U.S.C. §119(e) of U.S. Provisional Application No. 60/727,419,filed Oct. 17, 2005, and U.S. Provisional Patent Application No.60/759,525, filed Jan. 17, 2006, the disclosure of which is incorporatedherein by reference.

BACKGROUND OF THE INVENTION

This application relates to use of a composition comprising ahydroxy-oligocarboxylic ester for topical administration to alleviate orimprove cosmetic conditions, dental conditions, dermatologicalindications and other conditions in which the effects on the nervoussystem can be beneficial, particularly with respect to sensuous and mildanesthetic properties.

U.S. Pat. No. 5,091,171, entitled “Amphoteric Compositions and PolymericForms of Alpha Hydroxyacids, and Their Therapeutic Use,” describespreventive as well as therapeutic treatments to alleviate cosmeticconditions and symptoms of dermatologic disorders with amphotericcompositions containing alpha hydroxyacids, alpha ketoacids relatedcompounds or polymeric forms of hydroxyacids. U.S. Pat. No. 5,547,988,entitled “Alleviating Signs of Dermatological Aging with Glycolic Acid,Lactic Acid or Citric Acid,” describes the use of alpha-hydroxyacids toalleviate or improve signs of skin, nail and hair changes associatedwith intrinsic or extrinsic aging. U.S. Pat. No. 5,385,938, entitled“Method of Using Glycolic Acid for Treating Wrinkles,” describes the useof glycolic acid for topical treatment of wrinkles. U.S. Pat. No.5,258,391, entitled “Phenyl Alpha Acyloxyalkanoic Acids, Derivatives andTheir Therapeutic Use,” describes the use of topical compositionscontaining phenyl alpha acyloxyalkanoic acids and derivatives to enhancethe keratinization of nails, skin, lips and other mucous membranes.

U.S. Pat. No. 5,665,776, entitled “Additives Enhancing Topical Actionsof Therapeutic Agents,” describes the use of hydroxycarboxylic acids toenhance the therapeutic effects of cosmetic or pharmaceutical agents.U.S. Pat. No. 5,686,489, entitled “Alpha Hydroxyacid Esters for SkinAging,” describes the use of alpha-hydroxyacid esters to increase skinthickness by stimulating biosynthesis of dermal components such asglycosaminoglycans, proteoglycans, collagen and elastin, and to treataging related integumental changes including age spots, skin lines,wrinkles, photoaging and aging skin. U.S. Pat. No. 5,889,054, entitled“Method of Using Beta Hydroxyacids for Treating Wrinkles,” describes theuse of compositions comprising a beta-hydroxyacid for topical treatmentof skin changes associated with aging. U.S. Pat. No. 6,060,512, entitled“Method of Using Hydroxycarboxylic Acids or Related Compounds forTreating Skin Changes Associated with Intrinsic and Extrinsic Aging,”describes the use of compositions comprising a hydroxycarboxylic acidfor topical treatment of skin changes associated with intrinsic andextrinsic aging. U.S. Pat. Nos. 6,335,023 and 6,740,327, both entitled“Oligosaccharide Aldonic Acids and Their Topical Use,” describe the useof compositions comprising an oligosaccharide aldonic acid for topicaltreatment of cosmetic conditions and dermatological disorders. U.S. Pat.No. 6,767,924, entitled “Method of Using Hydroxycarboxylic Acids orRelated Compounds for Treating Skin Changes Associated with Intrinsicand Extrinsic Aging,” describes the use of compositions comprising apolyhydroxy acid in an amphoteric system for topical treatment of skinchanges associated with intrinsic and extrinsic aging.

None of the above patents has described or implied actions or effects ona nerve or nerves by topical administration of a hydroxyoligocarboxylicester, such as a hydroxydicarboxylic ester or a hydroxytricarboxylicester.

BRIEF SUMMARY OF THE INVENTION

While a hydroxy-monocarboxylic ester does not have effects on nerves,one aspect of the invention is based on the discovery of sensuous andmild anesthetic effects produced by a hydroxy-oligocarboxylic ester,preferably a hydroxydicarboxylic ester and more preferably ahydroxytricarboxylic ester, after topical application to mucocutaneousorgans or sites such as lips, and the use for cosmetic or dentalconditions, dermatological indications or another condition in which theeffects on the nervous system can be beneficial.

Another aspect of the invention is a method of using a compositioncomprising a hydroxy-oligocarboxylic ester for topical administration toalleviate or improve a disorder, symptom or syndrome associated with anervous, cutaneous or dental system including pain, pruritus,inflammation, erythema, dermatitis, eczema, psoriasis, and in woundhealing. The hydroxy-oligocarboxylic esters, preferablyhydroxydicarboxylic esters and more preferably the hydroxytricarboxylicesters, are anti-oxidant neutral compounds which include, for example,diethyl tartarate, triethyl citrate, tripropyl citrate and tri-isopropylcitrate.

Still another aspect of the invention is a method for producing abeneficial effect on a subject's nerve associated with at least one of acosmetic condition, a dermatological indication and a dental indicationand another condition, the method comprising topically applying to thesubject in a region where the beneficial effect is desired ahydroxy-oligocarboxylic ester in an amount effective to produce thebeneficial effect.

Yet another aspect is a method for producing a beneficial effect on asubject's nerve associated with at least one of a cosmetic condition, adermatological indication and a dental indication and another condition,the method comprising topically applying to the subject in a regionwhere the beneficial effect is desired a hydroxy-oligocarboxylic esterin an amount effective to produce the beneficial effect, wherein thebeneficial effect is at least one of a sensuous effect and a mildanesthetic effect on the nerve.

DEFINITIONS

As used herein, the singular forms “a”, “an”, and “the” include pluralreferents unless the context clearly dictates otherwise. For example,reference to a disorder, condition, indication, symptom or syndromemeans one or more such disorders, conditions, indications, symptoms orsyndromes.

As used herein, the term “beneficial effect” means an effect that isdesired for an intended benefit, whether an inhibitory effect to preventor alleviate a condition, or a desired positive effect, such as anenhanced and typically pleasurable sensuous or sensational or arousaleffect.

As used herein, a “mild anesthetic effect” is an effect in which theanesthetized nerve, organ or tissue still has some degree of feeling,such that the degree of feeling has a beneficial effect.

As used herein, a “sensuous effect” is an effect in feeling of arousingor preoccupying with gratification of the senses, and the degree offeeling has a beneficial effect.

As used herein, the terms “treatment,” “treating,” and the like, referto obtaining a desired beneficial effect, which may be a pharmacologic,physiologic, dermatologic and/or sensuous effect. The beneficial effectmay be prophylactic in terms of completely or partially preventing acondition or disease or symptom thereof and/or may be therapeutic interms of a partial or complete cure for a condition or disease and/oradverse affect attributable to the condition or disease, and/or causingan enhanced sensuous effect in the case of a sensuous treatment.“Treatment” or “treating” thus, for example, covers any treatment of acondition or disease in an animal, preferably in a mammal, and morepreferably in a human, and includes: (a) preventing the condition ordisease from occurring in a subject which may be predisposed to thecondition or disease but has not yet been diagnosed as having it; (b)inhibiting the condition or disease, such as, arresting its development;and (c) relieving, alleviating or ameliorating the condition or disease,such as, for example, causing regression of the condition or disease;all in the case where the beneficial effect is a desired inhibitoryeffect. “Treatment” or “treating” also includes creating the existenceof or enhancing a sensuous condition where the beneficial effect is adesired positive enhancement of a sensuous, sensational or arousaleffect.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the discovery that topical applicationof a hydroxy-oligocarboxylic ester, preferably a hydroxydicarboxylicester or more preferably a hydroxytricarboxylic ester such as tripropylcitrate on topical application can produce sensuous, sensational andmild anesthetic effects on mucocutaneous organs or sites, such as lips,mouth, gum, nostrils, nipples, vulva, vagina, penis and anus. We havealso found in contrast that a hydroxy-monocarboxylic ester, such asethyl glycolate and ethyl lactate does not produce a sensuous or mildanesthetic effect under the same conditions. The sensuous andsensational effects produced by the hydroxy-oligocarboxylic ester,preferably a hydroxydicarboxylic ester or more preferably ahydroxytricarboxylic ester are quite different from the numbing effectsinduced by local anesthetics such as lidocaine and procaine. Thesensuous, sensational and mild anesthetic effects produced by thehydroxy-oligocarboxylic ester according to the present inventiongenerally last from a few minutes to a few hours. Such nerve-actingsensation or effect has many cosmetic, dental and dermatologicalapplications. For example, a lipstick or lip balm comprising ahydroxy-oligocarboxylic ester, preferably a hydroxydicarboxylic ester ormore preferably a hydroxytricarboxylic ester, can provide a sensuous orsensational feeling after topical application to lips of a humansubject. Such sensuous action and certain anesthetic effects on nervoussystem produced by the hydroxy-oligocarboxylic ester can have beneficialapplications such as to relieve itch or pain of lips, mouth, gum,nostrils, nipples, vulva, vagina, penis and anus, and for conditionsassociated with eczema, hemorrhoids, dry or aging-associated changes ofthe vulva and vagina.

One aspect of the invention is a method for producing a beneficialeffect on a subject's nerve associated with at least one of a cosmeticcondition, a dermatological indication and a dental indication andanother condition, the method comprising topically applying to thesubject in a region where the beneficial effect is desired ahydroxy-oligocarboxylic ester in an amount effective to produce thebeneficial effect.

Another aspect is a method for producing a beneficial effect on asubject's nerve associated with at least one of a cosmetic condition, adermatological indication and a dental indication and another condition,the method comprising topically applying to the subject in a regionwhere the beneficial effect is desired a hydroxy-oligocarboxylic esterin an amount effective to produce the beneficial effect, wherein thebeneficial effect is at least one of a sensuous effect and a mildanesthetic effect on the nerve.

The hydroxy-oligocarboxylic ester includes at least one of diethylmalate, triethyl citrate, tripropyl citrate, tri-isopropyl citrate,diethyl glucate and dipropyl glucate, and any combination thereof.

Another aspect of the invention is the use of a hydroxy-oligocarboxylicester, preferably a hydroxydicarboxylic ester or more preferably ahydroxytricarboxylic ester, to heal and relieve pains, infections,inflammations associated with wound healing and disorders ofmucocutaneous organs or sites such as canker sores and toothache. Forthe mouth diseases, the hydroxy-oligocarboxylic ester is formulated as asolution or gel for mouth wash, gargle or rubbing.

The hydroxy-oligocarboxylic ester of the present invention is ananti-oxidant neutral compound. Yet another aspect of the invention isthe use of the anti-oxidant hydroxy-oligocarboxylic ester, preferably ahydroxydicarboxylic ester or more preferably a hydroxytricarboxylicester, as preventive care or treatment for damage, stinging orirritation of mucocutaneous organs or sites, skin, hair or nails causedby sunlight, chemicals, laser treatment, free radicals, electromagneticradiation, ionizing radiation such as alpha rays, beta rays, X-rays,gamma rays or other oxidative damages.

Yet another aspect of the invention is the use of ahydroxy-oligocarboxylic ester on cutaneous or mucocutaneous organs,sites or lesions for topical prevention or treatment of cosmeticconditions or dermatological indications selected from the groupconsisting of acne; rosacea; blemished skin; cellulite; dermatoses;dermatitis; skin or nail infections; dandruff; dry skin; xerosis;eczema; herpes; ichthyosis; pseudofolliculitis barbae; pruritus;psoriasis; stretch marks; warts; oral or gum disease; irritated,inflamed, unhealthy, damaged or abnormal mucosa, skin, hair, nail,nostril, ear canal, anal or vaginal conditions; uneven and rough surfaceof skin, nail and hair; reactive, irritating or telangiectatic skin; forskin bleach and lightening; and wound healing.

The hydroxy-oligocarboxylic esters of the present invention represent agroup of organic compounds which contain one or more hydroxyl groups andtwo to ten carboxyl groups in the molecules. The preferredhydroxy-oligocarboxylic esters contain one or more hydroxyl groups andtwo to three carboxyl groups in the molecules. The most preferredhydroxy-oligocarboxylic esters contain one or more hydroxyl groups andthree carboxyl groups in the molecules, such as triethyl citrate andtripropyl citrate.

The hydroxy-oligocarboxylic esters of the present invention can bedescribed as follows.

(A) Hydroxydicarboxylic Ester

Hydroxydicarboxylic ester can be divided into two groups; one ismonohydroxydicarboxylic ester and the other is dihydroxydicarboxylicester.

(1) Monohydroxydicarboxylic Ester

Monohydroxydicarboxylic ester comprises one hydroxyl group and twocarboxyl groups. The generic structure can be represented as thefollowing Formula I:

R₁OOC C(OH)R₂CHR₄COOR₃  (I)

wherein R₁ and R₃ are independently an alkyl group having 1 to 19 carbonatoms, or an aralkyl or aryl group having 6 to 19 carbon atoms; R₂ andR₄ are independently H, an alkyl group having 1 to 19 carbon atoms, oran aralkyl or aryl group having 6 to 19 carbon atoms; the H attached toany carbon atom can be substituted by I, F, Cl, Br or an alkoxyl grouphaving 1 to 19 carbons. The monohydroxydicarboxylic ester can be presentas saturated or unsaturated, stereoisomeric or non-stereoisomeric,straight or branched chain or cyclic form.

If the generic structure of Formula I cannot cover a specificmonohydroxydicarboxylic ester, the compound will be represented by itschemical name.

The following are representative hydroxydicarboxylic esters:

2-hydroxybutane-1,4-dioate esters (malate esters): dimethyl malate,diethyl malate, dipropyl malate, di-isopropyl malate, diamyl malate,dioctyl malate, di-isooctyl malate and dibenzyl malate.

2-hydroxy-2-methyl-butane-1,4-dioate esters (citramalate esters):dimethyl citramalate, diethyl citramalate, dipropyl citramalate,di-isopropyl citramalate, diamyl citramalate, dioctyl citramalate,di-isooctyl citramalate and dibenzyl citramalate.

(2) Dihydroxydicarboxylic Ester

Dihydroxydicarboxylic ester comprises two hydroxyl groups and twocarboxyl groups. The generic structure can be represented as thefollowing Formula II:

R₁OOC C(OH)R₂C(OH)R₄COOR₃  (II)

wherein R₁ and R₃ are independently an alkyl group having 1 to 19 carbonatoms, or an aralkyl or aryl group having 6 to 19 carbon atoms; R₂ andR₃ are independently H, an alkyl group having 1 to 19 carbon atoms, oran aralkyl or aryl group having 6 to 19 carbon atoms; the H attached toany carbon atom can be substituted by I, F, Cl, Br or an alkoxyl grouphaving 1 to 19 carbons. The dihydroxydicarboxylic ester can be presentas saturated or unsaturated, stereoisomeric or non-stereoisomeric,straight or branched chain or cyclic form.

If the generic structure of Formula II cannot cover a specificdihydroxydicarboxylic ester, the compound will be represented by itschemical name.

The following are representative dihydroxydicarboxylic esters:

2,3-dihydroxybutane-1,4-dioate esters (tartarate esters): dimethyltartarate, diethyl tartarate, dipropyl tartarate, di-isopropyltartarate, diamyl tartarate, dioctyl tartarate, di-isooctyl tartarateand dibenzyl tartarate.

(B) Hydroxytricarboxylic Ester

Hydroxytricarboxylic ester can be divided into three groups; (1)monohydroxytricarboxylic ester, (2) dihydroxytricarboxylic ester and (3)trihydroxytricarboxylic ester.

(1) Monohydroxytricarboxylic Ester

Monohydroxytricarboxylic ester comprises one hydroxyl group and threecarboxyl groups, and can be divided into four groups, (a) citrate ester,(b) isocitrate ester, (c) homocitrate ester and (d) homoisocitrateester.

(a) Citrate Ester

The generic structure of citrate ester can be represented as thefollowing Formula III:

R₁OOC CHR₂C(OH)(COOR₃) CHR₄COOR₃  (III)

wherein R₁, R₃ and R₅ are independently an alkyl group having 1 to 19carbon atoms, or an aralkyl or aryl group having 6 to 19 carbon atoms;R₂ and R₄ are independently H, an alkyl group having 1 to 19 carbonatoms, or an aralkyl or aryl group having 6 to 19 carbon atoms; the Hattached to any carbon atom can be substituted by I, F, Cl, Br or analkoxyl group having 1 to 19 carbons. The citrate ester can be presentas saturated or unsaturated, stereoisomeric or non-stereoisomeric,straight or branched chain or cyclic form.

If the generic structure of Formula III cannot cover a specific citrateester, the compound will be represented by its chemical name.

The following are representative citrate esters:

3-hydroxy-3-carboxypentane-1,5-dioate esters (citrate esters): trimethylcitrate, triethyl citrate, tripropyl citrate, tri-isopropyl citrate,triamyl citrate, trioctyl citrate, tri-isooctyl citrate, tribenzylcitrate and trinicotinyl citrate.

2-n-hexadecyl-3-hydroxy-3-carboxypentane-1,5-dioate esters (agaricateesters, n-hexadecyl citrate esters): trimethyl agaricate, triethylagaricate, tripropyl agaricate, tri-isopropyl agaricate, triamylagaricate, trioctyl agaricate, tri-isooctyl agaricate, tribenzylagaricate and trinicotinyl agaricate.

(b) Isocitrate Ester

The generic structure of isocitrate ester can be represented as thefollowing Formula IV:

R₁OOC C(OH)R₂CR₄(COOR₃) CHR₆COOR₅  (IV)

wherein R₁, R₃ and R₅ are independently an alkyl group having 1 to 19carbon atoms, or an aralkyl or aryl group having 6 to 19 carbon atoms;R₂, R₄ and R₆ are independently H, an alkyl group having 1 to 19 carbonatoms, or an aralkyl or aryl group having 6 to 19 carbon atoms; the Hattached to any carbon atom can be substituted by I, F, Cl, Br or analkoxyl group having 1 to 19 carbons. The isocitrate ester can bepresent as saturated or unsaturated, stereoisomeric ornon-stereoisomeric, straight or branched chain or cyclic form.

If the generic structure of Formula IV cannot cover a specificisocitrate ester, the compound will be represented by its chemical name.

The following are representative isocitrate esters:

2-hydroxy-3-carboxypentane-1,5-dioate esters (isocitrate esters):trimethyl isocitrate, triethyl isocitrate, tripropyl isocitrate,tri-isopropyl isocitrate, triamyl isocitrate, trioctyl isocitrate,tri-isooctyl isocitrate, tribenzyl isocitrate and trinicotinylisocitrate.

(c) Homocitrate Ester

The generic structure of homocitrate ester can be represented as thefollowing Formula V:

R₁OOC CHR₂C(OH)(COOR₃)CHR₄CHR₆COOR₅  (V)

wherein R₁, R₃ and R₅ are independently an alkyl group having 1 to 19carbon atoms, or an aralkyl or aryl group having 6 to 19 carbon atoms;R₂, R₄ and R₆ are independently H, an alkyl group having 1 to 19 carbonatoms, or an aralkyl or aryl group having 6 to 19 carbon atoms; the Hattached to any carbon atom can be substituted by I, F, Cl, Br or analkoxyl group having 1 to 19 carbons. The homocitrate ester can bepresent as saturated or unsaturated, stereoisomeric ornon-stereoisomeric, straight or branched chain or cyclic form.

If the generic structure of Formula V cannot cover a specifichomocitrate ester, the compound will be represented by its chemicalname.

The following are representative homocitrate esters:

3-hydroxy-3-carboxyhexane-1,6-dioate esters (homocitrate esters):trimethyl homocitrate, triethyl homocitrate, tripropyl homocitrate,tri-isopropyl homocitrate, triamyl homocitrate, trioctyl homocitrate,tri-isooctyl homocitrate, tribenzyl homocitrate and trinicotinylhomocitrate.

(d) Homoisocitrate Ester

The generic structure of homoisocitrate ester can be represented as thefollowing Formula VI:

R₁OOC C(OH)R₂CR₄(COOR₃)CHR₆CHR,COOR₅  (VI)

wherein R₁, R₃ and R₅ are independently an alkyl group having 1 to 19carbon atoms, or an aralkyl or aryl group having 6 to 19 carbon atoms;R₂, R₄, R₆ and R₇ are independently H, an alkyl group having 1 to 19carbon atoms, or an aralkyl or aryl group having 6 to 19 carbon atoms;the H attached to any carbon atom can be substituted by I, F, Cl, Br oran alkoxyl group having 1 to 19 carbons. The homoisocitrate ester can bepresent as saturated or unsaturated, stereoisomeric ornon-stereoisomeric, straight or branched chain or cyclic form.

If the generic structure of Formula VI cannot cover a specifichomoisocitrate ester, the compound will be represented by its chemicalname.

The following are representative homoisocitrate esters:

2-hydroxy-3-carboxyhexane-1,6-dioate esters (homoisocitrate esters):trimethyl homoisocitrate, triethyl homoisocitrate, tripropylhomoisocitrate, tri-isopropyl homoisocitrate, triamyl homoisocitrate,trioctyl homoisocitrate, tri-isooctyl homoisocitrate, tribenzylhomoisocitrate and trinicotinyl homoisocitrate.

(2) Dihydroxytricarboxylic Ester

Dihydroxytricarboxylic ester comprises two hydroxyl groups and threecarboxyl groups. There are five subgroups of dihydroxytricarboxylicesters: (a) hydroxycitrate ester; (b) hydroxyisocitrate ester; (c)hydroxyhomocitrate ester; (d) hydroxyhomoisocitrate ester; and (e)4,5-dihydroxy-3-carboxyhexane-1,6-dioate ester.

(a) Hydroxycitrate Ester

The generic structure can be represented as the following Formula VII:

R₁OOC C(OH)R₂C(OH)(COOR₃)CHR₄COOR₅  (VII)

wherein R₁, R₃ and R₅ are independently an alkyl group having 1 to 19carbon atoms, or an aralkyl or aryl group having 6 to 19 carbon atoms;R₂ and R₄ are independently H, an alkyl group having 1 to 19 carbonatoms, or an aralkyl or aryl group having 6 to 19 carbon atoms; the Hattached to any carbon atom can be substituted by I, F, Cl, Br or analkoxyl group having 1 to 19 carbons. The hydroxycitrate ester can bepresent as saturated or unsaturated, stereoisomeric ornon-stereoisomeric, straight or branched chain or cyclic form.

If the generic structure of Formula VII cannot cover a specifichydroxycitrate ester, the compound will be represented by its chemicalname.

The following are representative hydroxycitrate esters:

2,3-dihydroxy-3-carboxypentane-1,5-dioate esters (hydroxycitrateesters): trimethyl hydroxycitrate, triethyl hydroxycitrate, tripropylhydroxycitrate, tri-isopropyl hydroxycitrate, triamyl hydroxycitrate,trioctyl hydroxycitrate, tri-isooctyl hydroxycitrate, tribenzylhydroxycitrate and trinicotinyl hydroxycitrate.

2-n-hexadecyl-2,3-dihydroxy-3-carboxypentane-1,5-dioate esters and4-n-hexadecyl-2,3-dihydroxy-3-carboxypentane-1,5-dioate esters(hydroxyagaricate esters, n-hexadecyl hydroxycitrate esters): trimethylhydroxyagaricate, triethyl hydroxyagaricate, tripropyl hydroxyagaricate,tri-isopropyl hydroxyagaricate, triamyl hydroxyagaricate, trioctylhydroxyagaricate, tri-isooctyl hydroxyagaricate, tribenzylhydroxyagaricate and trinicotinyl hydroxyagaricate.

(b) Hydroxyisocitrate Ester

The generic structure can be represented as the following Formula VIII:

R₁OOC C(OH)R₂CR₄(COOR₃)C(OH)R₆COOR₅  (VIII)

wherein R₁, R₃ and R₅ are independently an alkyl group having 1 to 19carbon atoms, or an aralkyl or aryl group having 6 to 19 carbon atoms;R₂, R₄ and R₆ are independently H, an alkyl group having 1 to 19 carbonatoms, or an aralkyl or aryl group having 6 to 19 carbon atoms; the Hattached to any carbon atom can be substituted by I, F, Cl, Br oralkoxyl group having 1 to 19 carbons. The hydroxyisocitrate ester can bepresent as saturated or unsaturated, stereoisomeric ornon-stereoisomeric, straight or branched chain or cyclic form.

If the generic structure of Formula VIII cannot cover a specifichydroxyisocitrate ester, the compound will be represented by itschemical name.

The following are representative hydroxyisocitrate esters.

2,4-dihydroxy-3-carboxypentane-1,5-dioate esters (hydroxyisocitrateesters): trimethyl hydroxyisocitrate, triethyl hydroxyisocitrate,tripropyl hydroxyisocitrate, tri-isopropyl hydroxyisocitrate, triamylhydroxyisocitrate, trioctyl hydroxyisocitrate, tri-isooctylhydroxyisocitrate, tribenzyl hydroxyisocitrate and trinicotinylhydroxyisocitrate.

(c) Hydroxyhomocitrate Ester

Due to the position of the second hydroxyl group, there are threegeneric structures which can be represented as the following FormulasIX, X and XI:

R₁OOC C(OH)R₂C(OH)(COOR₃)CHR₄CHR₆COOR₅  (IX)

R₁OOC CHR₂C(OH)(COOR₃)C(OH)R₄CHR₆COOR₅  (X)

R₁OOC CHR₂C(OH)(COOR₃)CHR₄C(OH)R₆COOR₅  (XI)

wherein, in each of the Formulas IX, X and XI, R₁, R₃ and R₅ areindependently an alkyl group having 1 to 19 carbon atoms, or an aralkylor aryl group having 6 to 19 carbon atoms; R₂, R₄ and R₆ areindependently H, an alkyl group having 1 to 19 carbon atoms, or anaralkyl or aryl group having 6 to 19 carbon atoms; the H attached to anycarbon atom can be substituted by I, F, Cl, Br or alkoxyl group having 1to 19 carbons. The hydroxyhomocitrate ester can be present as saturatedor unsaturated, stereoisomeric or non-stereoisomeric, straight orbranched chain or cyclic form.

If the generic structures of Formulas IX, X or XI cannot cover aspecific hydroxyhomocitrate ester, the compound will be represented byits chemical name.

The following are representative hydroxyhomocitrate esters:

2,3-dihydroxy-3-carboxyhexane-1,6-dioate esters;3,4-dihydroxy-3-carboxyhexane-1,6-dioate esters; and3,5-dihydroxy-3-carboxyhexane-1,6-dioate esters (hydroxyhomocitrateesters): trimethyl hydroxyhomocitrate, triethyl hydroxyhomocitrate,tripropyl hydroxyhomocitrate, tri-isopropyl hydroxyhomocitrate, triamylhydroxyhomocitrate, trioctyl hydroxyhomocitrate, tri-isooctylhydroxyhomocitrate, tribenzyl hydroxyhomocitrate and trinicotinylhydroxyhomocitrate.

(d) Hydroxyhomoisocitrate Ester

Due to the position of the second hydroxyl group, there are two genericstructures which can be represented as the following Formulas XII andXIII:

R₁OOC C(OH)R₂CR₄(COOR₃)C(OH)R₆CHR₇COOR₅  (XII)

R₁OOC C(OH)R₂CR₄(COOR₃)CHR₆C(OH)R₇COOR₅  (XIII)

wherein in each of the Formulas XII and XIII, R₁, R₃ and R₅ areindependently an alkyl group having 1 to 19 carbon atoms, or an aralkylor aryl group having 6 to 19 carbon atoms; R₂, R_(4,) R₆ and R₇ areindependently H, an alkyl group having 1 to 19 carbon atoms, or anaralkyl or aryl group having 6 to 19 carbon atoms; the H attached to anycarbon atom can be substituted by I, F, Cl, Br or an alkoxyl grouphaving 1 to 19 carbons. The hydroxyhomoisocitrate ester can be presentas saturated or unsaturated, stereoisomeric or non-stereoisomeric,straight or branched chain or cyclic form.

If the generic structures of Formulas XII or XIII cannot cover aspecific hydroxyhomoisocitrate ester, the compound will be representedby its chemical name.

The following are representative hydroxyhomoisocitrate esters:

2,4-dihydroxy-3-carboxyhexane-1,6-dioate esters and2,5-dihydroxy-3-carboxyhexane-1,6-dioate esters (hydroxyhomoisocitrateesters): trimethyl hydroxyhomoisocitrate, triethylhydroxyhomoisocitrate, tripropyl hydroxyhomoisocitrate, tri-isopropylhydroxyhomoisocitrate, triamyl hydroxyhomoisocitrate, trioctylhydroxyhomoisocitrate, tri-isooctyl hydroxyhomoisocitrate, tribenzylhydroxyhomoisocitrate and trinicotinyl hydroxyhomoisocitrate.

(e) 4,5-dihydroxy-3-carboxyhexane-1,6-dioate ester

The generic structure can be represented as the following Formula XIV:

R₁OOC CHR₂CR₄(COOR₃)C(OH)R₆C(OH)R₇COOR₅  (XIV)

wherein, R₁, R₃ and R₅ are independently an alkyl group having 1 to 19carbon atoms, or an aralkyl or aryl group having 6 to 19 carbon atoms;R₂, R_(4,) R₆ and R₇ are independently H, an alkyl group having 1 to 19carbon atoms, or an aralkyl or aryl group having 6 to 19 carbon atoms;the H attached to any carbon atom can be substituted by I, F, Cl, Br oran alkoxyl group having 1 to 19 carbons. The4,5-dihydroxy-3-carboxyhexane-1,6-dioate esters can be present assaturated or unsaturated, stereoisomeric or non-stereoisomeric, straightor branched chain or cyclic form.

If the generic structure of Formula XIV cannot cover a specific4,5-dihydroxy-3-carboxyhexane-1,6-dioate ester, the compound will berepresented by its chemical name.

The following are representative4,5-dihydroxy-3-carboxyhexane-1,6-dioate esters: trimethyl4,5-dihydroxy-3-carboxyhexane-1,6-dioate; triethyl4,5-dihydroxy-3-carboxyhexane-1,6-dioate; tripropyl4,5-dihydroxy-3-carboxyhexane-1,6-dioate; tri-isopropyl4,5-dihydroxy-3-carboxyhexane-1,6-dioate; triamyl4,5-dihydroxy-3-carboxyhexane-1,6-dioate; trioctyl4,5-dihydroxy-3-carboxyhexane-1,6-dioate; tri-isooctyl4,5-dihydroxy-3-carboxyhexane-1,6-dioate; tribenzyl4,5-dihydroxy-3-carboxyhexane-1,6-dioate and trinicotinyl4,5-dihydroxy-3-carboxyhexane-1,6-dioate.

(3) Trihydroxytricarboxylic Ester

Trihydroxytricarboxylic ester comprises three hydroxyl groups and threecarboxyl groups. There are three subgroups of trihydroxytricarboxylicesters: (a) dihydroxycitrate ester, (b) dihydroxyhomocitrate ester and(c) dihydroxyhomoisocitrate ester.

(a) Dihydroxycitrate Ester

The generic structure can be represented as the following Formula XV:

R₁OOC C(OH)R₂C(OH)(COOR₃)C(OH)R₄COOR₅  (XV)

wherein R₁, R₃ and R₅ are independently an alkyl group having 1 to 19carbon atoms, or an aralkyl or aryl group having 6 to 19 carbon atoms;R₂ and R₄ are independently H, an alkyl group having 1 to 19 carbonatoms, or an aralkyl or aryl group having 6 to 19 carbon atoms; the Hattached to any carbon atom can be substituted by I, F, Cl, Br or analkoxyl group having 1 to 19 carbons. The dihydroxycitrate ester can bepresent as saturated or unsaturated, stereoisomeric ornon-stereoisomeric, straight or branched chain or cyclic form.

If the generic structure of Formula XV cannot cover a specificdihydroxycitrate ester, the compound will be represented by its chemicalname.

The following are representative dihydroxycitrate esters:2,3,4-trihydroxy-3-carboxypentane-1,5-dioate esters (dihydroxycitrateesters): trimethyl dihydroxycitrate, triethyl dihydroxycitrate,tripropyl dihydroxycitrate, tri-isopropyl dihydroxycitrate, triamyldihydroxycitrate, trioctyl dihydroxycitrate, tri-isooctyldihydroxycitrate, tribenzyl dihydroxycitrate and trinicotinyldihydroxycitrate.

(b) Dihydroxyhomocitrate Ester

Due to the positions of the second and third hydroxyl groups, there arethree generic structures which can be represented as the followingFormulas XVI, XVII and XVIII:

R₁OOC C(OH)R₂C(OH)(COOR₃)C(OH)R₄CHR₆COOR₅  (XVI)

R₁OOC C(OH)R₂C(OH)(COOR₃)CHR₄C(OH)R₆COOR₅  (XVII)

R₁OOC CHR₂C(OH)(COOR₃)C(OH)R₄C(OH)R₆COOR₅  (XVIII)

wherein in each of the Formulas XVI, XVII and XVIII, R₁, R₃ and R₅ areindependently an alkyl group having 1 to 19 carbon atoms, or an aralkylor aryl group having 6 to 19 carbon atoms; R₂, R₄ and R₆ areindependently H, an alkyl group having 1 to 19 carbon atoms, or anaralkyl or aryl group having 6 to 19 carbon atoms; the H attached to anycarbon atom can be substituted by I, F, Cl, Br or an alkoxyl grouphaving 1 to 19 carbons. The dihydroxyhomocitrate ester can be present assaturated or unsaturated, stereoisomeric or non-stereoisomeric, straightor branched chain or cyclic form.

If the generic structures of Formulas XVI, XVII or XVIII cannot cover aspecific dihydroxyhomocitrate ester, the compound will be represented byits chemical name.

The following are representative dihydroxyhomocitrate esters:

2,3,4-trihydroxy-3-carboxyhexane-1,6-dioate esters;2,3,5-trihydroxy-3-carboxyhexane-1,6-dioate esters and3,4,5-trihydroxy-3-carboxyhexane-1,6-dioate esters (dihydroxyhomocitrateesters): trimethyl dihydroxyhomocitrate, triethyl dihydroxyhomocitrate,tripropyl dihydroxyhomocitrate, tri-isopropyl dihydroxyhomocitrate,triamyl dihydroxyhomocitrate, trioctyl dihydroxyhomocitrate,tri-isooctyl dihydroxyhomocitrate, tribenzyl dihydroxyhomocitrate andtrinicotinyl dihydroxyhomocitrate.

(c) Dihydroxyhomoisocitrate Ester

The generic structure can be represented as the following Formula XIX:

R₁OOC C(OH)R₂CR₄(COOR₃)C(OH)R₆C(OH)R₇COOR₅  (XIX)

wherein R₁, R₃ and R₅ are independently an alkyl group having 1 to 19carbon atoms, or an aralkyl or aryl group having 6 to 19 carbon atoms;R₂, R₄, R₆ and R₇ are independently H, an alkyl group having 1 to 19carbon atoms, or an aralkyl or aryl group having 6 to 19 carbon atoms;the H attached to any carbon atom can be substituted by I, F, Cl, Br oran alkoxyl group having 1 to 19 carbons. The dihydroxyhomoisocitrateester can be present as saturated or unsaturated, stereoisomeric ornon-stereoisomeric, straight or branched chain or cyclic form.

If the generic structure Formula XIX cannot cover a specificdihydroxyhomoisocitrate ester, the compound will be represented by itschemical name.

The following are representative dihydroxyhomoisocitrate esters:

2,4,5-trihydroxy-3-carboxyhexane-1,6-dioate esters(dihydroxyhomoisocitrate esters): trimethyl dihydroxyhomoisocitrate,triethyl dihydroxyhomoisocitrate, tripropyl dihydroxyhomoisocitrate,tri-isopropyl dihydroxyhomoisocitrate, triamyl dihydroxyhomoisocitrate,trioctyl dihydroxyhomoisocitrate, tri-isooctyl dihydroxyhomoisocitrate,tribenzyl dihydroxyhomoisocitrate and trinicotinyldihydroxyhomoisocitrate.

In general, we have found that sensuous and sensational effects producedby the hydroxytricarboxylic ester are much stronger and last longer thanthat produced by hydroxydicarboxylic ester. In the same family group ofhydroxytricarboxylic esters, we have also found that sensuous andsensational effects produced by the longer chain esters are muchstronger and last longer than those produced by the shorter chainesters. For example, tripropyl citrate produces much stronger andlonger-lasting sensuous and sensational effects than those produced bytrimethyl citrate.

Cosmetic, pharmaceutical and other topical agents can also beincorporated into a composition of the present invention for synergeticor synergistic effects. The topical agents include, for example withoutlimitation, hydroxyacids, ketoacids and related compounds; phenyl alphaacyloxyalkanoic acids and derivatives; N-acyl-aldosamines, N-acylaminoacids and related N-acyl compounds; local analgesics and anesthetics;anti-acne agents; anti-bacterial agents; anti-yeast agents; anti-fungalagents; anti-viral agents; anti-infective agents; anti-dandruff agents;anti-dermatitis agents; anti-eczema agents; anti-histamine agents;anti-pruritic agents; anti-emetics; anti-motion sickness agents;anti-inflammatory agents; anti-hyperkeratotic agents; antiperspirants;anti-psoriatic agents; anti-rosacea agents; anti-seborrheic agents; hairconditioners and hair treatment agents; anti-aging and anti-wrinkleagents; anti-anxiety agents; anti-convulsant agents; anti-depressantagents; sunblock and sunscreen agents; skin lightening agents;depigmenting agents; astringents; cleansing agents; corn, callus andwart removing agents; skin plumping agents; skin volumizing agents; skinfirming agents; matrix metalloproteinase (MMP) inhibitors; topicalcardiovascular agents; wound-healing agents; gum disease or oral careagents; amino acids; peptides; dipeptides; tripeptides; glutathione andits derivatives; oligopeptides; polypeptides;

carbohydrates; aminocarbohydrates; vitamins; corticosteroids; tanningagents; hormones and retinoids.

For synergetic or synergistic effects, the cosmetic, pharmaceutical andother topical agents also include, for example without limitation,abacavir, acebutolol, acetaminophen, acetaminosalol, acetazolamide,acetohydroxamic acid, acetylsalicylic acid, N-acylglutathione esters,acitretin, aclovate, acrivastine, actiq, acyclovir, adalimumab,adapalene, adefovir dipivoxil, adenosine, albuterol, alfuzosin,allopurinol, alloxanthine, almotriptan, alprazolam, alprenolol, aluminumacetate, aluminum chloride, aluminum chlorohydroxide, aluminumhydroxide, amantadine, amiloride, aminacrine, p-aminobenzoic acid,aminocaproic acid, aminolevulinic acid, aminosalicylic acid, amiodarone,amitriptyline, amlodipine, amocarzine, amodiaquin, amorolfine,amoxapine, amphetamine, ampicillin, anagrelide, anastrozole, anthralin,apomorphine, aprepitant, arbutin, aripiprazole, ascorbic acid, ascorbylpalmitate, atazanavir, atenolol, atomoxetine, atropine, azathioprine,azelaic acid, azelastine, azithromycin, bacitracin, beclomethasonedipropionate, bemegride, benazepril, bendroflumethiazide, benzocaine,benzonatate, benzophenone, benzoyl peroxide, benztropine, bepridil,betamethasone dipropionate, betamethasone valerate, brimonidine,brompheniramine, bupivacaine, buprenorphine, bupropion, burimamide,butenafine, butoconazole, cabergoline, caffeic acid, caffeine,calcipotriene, camphor, candesartan cilexetil, capsaicin, carbamazepine,carbamide peroxide, cefditoren pivoxil, cefepime, cefpodoxime proxetil,celecoxib, cetirizine, cevimeline, chitosan, chlordiazepoxide,chlorhexidine, chloroquine, chlorothiazide, chloroxylenol,chlorpheniramine, chlorpromazine, chlorpropamide, ciclopirox,cilostazol, cimetidine, cinacalcet, ciprofloxacin, citalopram, citricacid, cladribine, clarithromycin, clemastine, clindamycin, clioquinol,clobetasol propionate, clocortolone pivalate, clomiphene, clonidine,clopidogrel, clotrimazole, clozapine, coal tar, coal tar extracts (LCD),cocaine, codeine, cromolyn, crotamiton, cyclizine, cyclobenzaprine,cycloserine, cytarabine, dacarbazine, dalfopristin, dapsone, daptomycin,daunorubicin, deferoxamine, dehydroepiandrosterone, delavirdine,desipramine, desloratadine, desmopres sin, desoximetasone,dexamethasone, dexmedetomidine, dexmethylphenidate, dexrazoxane,dextroamphetamine, diazepam, diclofenac, dicyclomine, didanosine,dihydrocodeine, dihydromorphine, diltiazem, 6,8-dimercaptooctanoic acid(dihydrolipoic acid), diphenhydramine, diphenoxylate, dipyridamole,disopyramide, dobutamine, dofetilide, dolasetron, donepezil, dopaesters, dopamide, dopamine, dorzolamide, doxepin, doxorubicin,doxycycline, doxylamine, doxypin, duloxetine, dyclonine, econazole,efalizumab, eflornithine, eletriptan, emtricitabine, enalapril,ephedrine, epinephrine, epinine, epirubicin, eptifibatide, ergotamine,erythromycin, escitalopram, esmolol, esomeprazole, estazolam, estradiol,etanercept, ethacrynic acid, ethinyl estradiol, etidocaine, etomidate,famciclovir, famotidine, felodipine, fentanyl, ferulic acid,fexofenadine, flecainide, fluconazole, flucytosine, fluocinoloneacetonide, fluocinonide, 5-fluorouracil, fluoxetine, fluphenazine,flurazepam, fluticasone propionate, fluvoxamine, formoterol, furosemide,galactarolactone, galactonic acid, galactonolactone, galantamine,gatifloxacin, gefitinib, gemcitabine, gemifloxacin, glucarolactone,gluconic acid, gluconolactone, glucuronic acid, glucuronolactone,glycolic acid, griseofulvin, guaifenesin, guanethidine,N-guanylhistamine, haloperidol, haloprogin, hexylresorcinol,homatropine, homosalate, hydralazine, hydrochlorothiazide,hydrocortisone, hydrocortisone 21-acetate, hydrocortisone 17-butyrate,hydrocortisone 17-valerate, hydrogen peroxide, hydromorphone,hydroquinone, hydroquinone monoether, hydroxyzine, hyoscyamine,hypoxanthine, ibuprofen, ichthammol, idarubicin, imatinib, imipramine,imiquimod, indinavir, indomethacin, infliximab, irbesartan, irinotecan,isoetharine, isoproterenol, itraconazole, kanamycin, ketamine,ketanserin, ketoconazole, ketoprofen, ketotifen, kojic acid, labetalol,lactic acid, lactobionic acid, lamivudine, lamotrigine, lansoprazole,letrozole, leuprolide, levalbuterol, levofloxacin, lidocaine, linezolid,lobeline, loratadine, loperamide, losartan, loxapine, lysergicdiethylamide, mafenide, malic acid, maltobionic acid, mandelic acid,maprotiline, mebendazole, mecamylamine, meclizine, meclocycline,memantine, menthol, meperidine, mepivacaine, mequinol, mercaptopurine,mescaline, metanephrine, metaproterenol, metaraminol, metformin,methadone, methamphetamine, methotrexate, methoxamine, methyldopaesters, methyldopamide, 3,4-methylenedioxymethamphetamine, methyllacticacid, methyl nicotinate, methylphenidate, methyl salicylate, metiamide,metolazone, metoprolol, metronidazole, mexiletine, miconazole,midazolam, midodrine, miglustat, minocycline, minoxidil, mirtazapine,mitoxantrone, moexiprilat, molindone, monobenzone, morphine,moxifloxacin, moxonidine, mupirocin, nadolol, naftifine, nalbuphine,nalmefene, naloxone, naproxen, nefazodone, nelfinavir, neomycin,nevirapine, nicardipine, nicotine, nifedipine, nimodipine, nisoldipine,nitrofurantoin, nizatidine, norepinephrine, nystatin, octopamine,octreotide, octyl methoxycinnamate, octyl salicylate, ofloxacin,olanzapine, olmesartan medoxomil, olopatadine, omeprazole, ondansetron,oxiconazole, oxotremorine, oxybenzone, oxybutynin, oxycodone,oxymetazoline, padimate O, palonosetron, pantothenic acid, pantoyllactone, paroxetine, pemoline, penciclovir, penicillamine, penicillins,pentazocine, pentobarbital, pentostatin, pentoxifylline, pergolide,perindopril, permethrin, phencyclidine, phenelzine, pheniramine,phenmetrazine, phenobarbital, phenol, phenoxybenzamine, phentolamine,phenylephrine, phenylpropanolamine, phenytoin, physostigmine,pilocarpine, pimecrolimus, pimozide, pindolol, pioglitazone, pipamazine,piperonyl butoxide, pirenzepine, podofilox, podophyllin, povidoneiodine, pramipexole, pramoxine, prazosin, prednisone, prenalterol,prilocaine, procainamide, procaine, procarbazine, promazine,promethazine, promethazine propionate, propafenone, propoxyphene,propranolol, propylthiouracil, protriptyline, pseudoephedrine,pyrethrin, pyrilamine, pyrimethamine, quetiapine, quinapril,quinethazone, quinidine, quinupristin, rabeprazole, reserpine,resorcinol, retinal, 13-cis retinoic acid, retinoic acid, retinol,retinyl acetate, retinyl palmitate, ribavirin, ribonic acid,ribonolactone, rifampin, rifapentine, rifaximin, riluzole, rimantadine,risedronic acid, risperidone, ritodrine, rivastigmine, rizatriptan,ropinirole, ropivacaine, salicylamide, salicylic acid, salmeterol,scopolamine, selegiline, selenium sulfide, serotonin, sertaconazole,sertindole, sertraline, shale tar, sibutramine, sildenafil, sotalol,streptomycin, strychnine, sulconazole, sulfacetamide, sulfabenz,sulfabenzamide, sulfabromomethazine, sulfacetamide (sodiumsulfacetamide), sulfachlorpyridazine, sulfacytine, sulfadiazine,sulfadimethoxine, sulfadoxine, sulfaguanole, sulfalene, sulfamethizole,sulfamethoxazole, sulfanilamide, sulfapyrazine, sulfapyridine,sulfasalazine, sulfasomizole, sulfathiazole, sulfisoxazole, sulfur,tacrolimus, tadalafil, tamsulosin, tartaric acid, tazarotene, tegaserol,telithromycin, telmisartan, temozolomide, tenofovir disoproxil,terazosin, terbinafine, terbutaline, terconazole, terfenadine,tetracaine, tetracycline, tetrahydrozoline, thalidomide, theobromine,theophylline, thiabendazole, thioctic acid (lipoic acid), thioridazine,thiothixene, thymol, tiagabine, timolol, tinidazole, tioconazole,tirofiban, tizanidine, tobramycin, tocainide, tolazoline, tolbutamide,tolnaftate, tolterodine, tramadol, tranylcypromine, trazodone,triamcinolone acetonide, triamcinolone diacetate, triamcinolonehexacetonide, triamterene, triazolam, triclosan, triflupromazine,trimethoprim, trimipramine, tripelennamine, triprolidine, tromethamine,tropic acid, tyramine, undecylenic acid, urea, urocanic acid, ursodiol,vardenafil, venlafaxine, verapamil, vitamin E acetate, voriconazole,warfarin, wood tar, xanthine, zafirlukast, zaleplon, zinc pyrithione,ziprasidone, zolmitriptan and zolpidem.

General Preparations

Compositions comprising a hydroxyl-oligocarboxylic ester, preferably ahydroxydicarboxylic ester, and more preferably a hydroxytricarboxylicester, of the present invention can be formulated as solution, gel,lotion, cream, ointment, shampoo, spray, stick, pads, powder, masque,mouth rinse or wash, vaginal gel or preparation, or other formacceptable for use on mucocutaneous sites or the like, such as oralmucosa, lips, nostrils, vulva, vagina, penis, anus and nipples.

To prepare a solution composition, at least one hydroxy-oligocarboxylicester, preferably a hydroxydicarboxylic ester, and more preferably ahydroxytricarboxylic ester, is dissolved in a solution prepared fromwater, ethanol, propylene glycol, butylene glycol, and/or othertopically acceptable vehicle. The concentration of thehydroxy-oligocarboxylic ester can be about 0.1% to about 100% by weightof the total composition, with a preferred concentration of about 1% toabout 40% by weight of the total composition, and with more preferredconcentration of about 2% to about 20% by weight of the totalcomposition.

To prepare a topical composition in lotion, cream or ointment form, theliquid form hydroxy-oligocarboxylic ester can be mixed directly with adesired base or can be first dissolved in ethanol, propylene glycol,and/or other solvent and the solution thus obtained is mixed with adesired base or pharmaceutically acceptable vehicle to make a lotion,cream or ointment. The concentration is the same as described above.

A topical composition of the instant invention can also be formulated ina gel form. A typical gel composition is formulated by the addition of agelling agent, such as chitosan, methyl cellulose, ethyl cellulose,polyvinyl alcohol, polyquaterniums, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer orammoniated glycyrrhizinate, to a solution comprising thehydroxy-oligocarboxylic ester of the present invention. The preferredconcentration of the gelling agent may be about 0.2% to about 2% byweight of the total composition.

To prepare a topical combination composition for synergetic orsynergistic effects, a cosmetic, pharmaceutical or other topicallyactive agent is incorporated into any one of the above compositions bydissolving or mixing the agent into the formulation.

Other forms of compositions for delivery of the compound of the presentinvention may readily be blended, prepared or formulated by thoseskilled in the art in view of the present disclosure.

A composition comprising a hydroxy-oligocarboxylic ester, preferably ahydroxydicarboxylic ester, and more preferably a hydroxytricarboxylicester, can be topically applied to mucocutaneous organs or sites forsensual and sensational effects. The mucocutaneous organs or sitesinclude lips, mouth, gum, nostrils, nipples, vulva, vagina, penis andanus. As noted above, the sensuous and sensational effects produced bythe hydroxy-oligocarboxylic ester are quite different from the numbingeffects induced by local anesthetics such as lidocaine and procaine. Thesensuous and sensational effects produced by the hydroxy-oligocarboxylicester generally last from a few minutes to a few hours. For example, alipstick or lip balm comprising a hydroxydicarboxylic ester orpreferably hydroxytricarboxylic ester can provide sensuous orsensational feeling after topical application to lips of a humansubject. For instance, a cream or ointment containing 10% triethylcitrate, tripropyl citrate or triisopropyl citrate can be topicallyapplied to lips. After one to two minutes, the lips will experiencesensual and sensational pleasure with very mild anesthetic effects, andone feels that the lips are plumping up in size. Such feelings usuallylast for approximately 10 minutes to 2 hours.

Such actions on the nervous system are beneficial for many othercosmetic, dental and dermatological indications, such as to relieve itchor pain of lips, mouth, gum, nostrils, nipples, vulva, vagina, penis andanus, and for conditions associated with eczema, hemorrhoids, dry oraging-associated changes of the vulva and vagina.

A composition comprising a hydroxy-oligocarboxylic ester, preferably ahydroxydicarboxylic ester, and more preferably a hydroxytricarboxylicester, can also be topically applied to mucocutaneous or skin lesions.For example, a cream or ointment containing 10% tripropyl citrate ortri-isopropyl citrate can be topically applied to eczematous orpsoriatic lesions twice daily for 4 to 16 weeks. The itch associatedwith eczema or psoriasis usually disappears within a few minutes aftertopical application.

Another aspect of the invention is the use of a hydroxy-oligocarboxylicester, preferably a hydroxydicarboxylic ester, and more preferably ahydroxytricarboxylic ester, to relieve pain, infections and/orinflammations associated with wound healing and disorders ofmucocutaneous organs or sites such as canker sores and toothache. Forthe mouth diseases, the hydroxy-oligocarboxylic ester is formulated as asolution or gel form for mouth wash, gargle or rubbing.

In view of the anti-oxidant properties of the hydroxy-oligocarboxylicesters, yet another aspect of the invention is the use of them, andpreferably anti-oxidant hydroxydicarboxylic ester or more preferablyanti-oxidant hydroxytricarboxylic ester, as preventive care or treatmentfor damage, stinging or irritation of mucocutaneous organs or sites,skin, hair or nails caused by sunlight, chemicals, laser treatment, freeradicals, electromagnetic radiation, ionizing radiation such as alpharays, beta rays, X-rays, gamma rays or other oxidative damages.

Preferred embodiments of the invention will now be described in moredetail with respect to the following specific, non-limiting examples.

EXAMPLE 1

Ethyl glycolate 10 g was mixed with 90 g ointment prepared from whitepetrolatum 50 parts, mineral oil 40 parts and white beeswax 10 parts.The composition thus prepared contained 10% ethyl glycolate in ahydrophobic ointment that was not washable with water (awater-non-washable ointment).

A male subject, age 73, topically applied the above 10% ethyl glycolateointment on his lips. There was no sensual or sensational feelingsduring the next 30 minutes. This result shows that ahydroxy-monocarboxylic ester does not produce any actions on the nervein mucocutaneous sites.

EXAMPLE 2

L-Ethyl lactate 10 g was mixed with 90 g ointment prepared from whitepetrolatum 50 parts, mineral oil 40 parts and white beeswax 10 parts.The composition thus prepared contained 10% L-ethyl lactate inwater-non-washable ointment.

A male subject, age 73, topically applied the above 10% L-ethyl lactateointment on his lips. There was no sensual or sensational feelingsduring the next 30 minutes. This result shows that a differenthydroxy-monocarboxylic ester does not produce any actions on the nervein mucocutaneous sites.

EXAMPLE 3

DL-Diethyl malate 10 g was mixed with 90 g ointment prepared from whitepetrolatum 50 parts, mineral oil 40 parts and white beeswax 10 parts.The composition thus prepared contained 10% DL-diethyl malate in awater-non-washable ointment.

A male subject, age 73, topically applied the above 10% DL-diethylmalate ointment on his lips. After one to two minutes, the lipsexperienced sensual and plumping feelings which lasted for about 10 to20 minutes. Such action on the nerves of the lips shows ahydroxydicarboxylic ester can provide beneficial effect, representativeof other beneficial effects for various cosmetic conditions anddermatological indications.

EXAMPLE 4

D-Diethyl tartarate 10 g was mixed with 90 g ointment prepared fromwhite petrolatum 50 parts, mineral oil 40 parts and white beeswax 10parts. The composition thus prepared contained 10% D-diethyl tartaratein a water-non-washable ointment.

A male subject, age 73, topically applied the above 10% D-diethyltartarate ointment on his lips. After one to two minutes, the lipsexperienced slight sensual and plumping feelings which lasted for about10 to 20 minutes. Such action on the nerves of the lips shows that adihydroxydicarboxylic ester can provide a beneficial effect,representative of other beneficial effects for various cosmeticconditions and dermatological indications.

EXAMPLE 5

L-Diethyl tartarate 10 g was mixed with 90 g ointment prepared fromwhite petrolatum 50 parts, mineral oil 40 parts and white beeswax 10parts. The composition thus prepared contained 10% L-diethyl tartaratein a water-non-washable ointment.

A male subject, age 73, topically applied the above 10% L-diethyltartarate ointment on his lips. After one to two minutes, the lipsexperienced slight sensual and plumping feelings which lasted for about10 to 20 minutes. Such action on the nerves of the lips shows that adihydroxydicarboxylic ester can provide a beneficial effect,representative of other beneficial effects for various cosmeticconditions and dermatological indications.

EXAMPLE 6

Triethyl citrate 10 g and propylene glycol 10 ml were mixed withhydrophilic ointment or oil-in-water emulsion 80 g. The composition thusprepared contained 10% triethyl citrate in a water-soluble oil-in-wateremulsion.

A male subject, age 73, topically applied the above 10% triethyl citratecream on his lips. After one to two minutes, the lips experiencedsensual and plumping feelings which lasted for about 20-30 minutes. Suchaction on the nerves of the lips shows that a monohydroxytricarboxylicester can provide a beneficial effect, representative of otherbeneficial effects for various cosmetic conditions and dermatologicalindications.

EXAMPLE 7

Triethyl citrate 10 g was mixed with 90 g ointment prepared from whitepetrolatum 50 parts, mineral oil 40 parts and white beeswax 10 parts.The composition thus prepared contained 10% triethyl citrate in awater-non-washable ointment.

Seven volunteer subjects, four males and three females, topicallyapplied the above 10% triethyl citrate ointment on their lips. After oneto two minutes, the lips experienced sensual and plumping feelings whichlasted for about 20 to 30 minutes. Such action on the nerves of the lipsshows that a monohydroxytricarboxylic ester in a different formulationthan in Example 6 and used by several subjects can provide a beneficialeffect, representative of other beneficial effects for various cosmeticconditions and dermatological indications.

EXAMPLE 8

Triethyl citrate 10 g was mixed with 90 g ointment prepared from whitepetrolatum 50 parts, mineral oil 40 parts and white beeswax 10 parts.The composition thus prepared contained 10% triethyl citrate in awater-non-washable ointment.

A male subject, age 73, having atopic eczema with severe itching skintopically applied the above 10% triethyl citrate ointment to the itchingskin on his right lower leg. After a few minutes, the itch stopped, andthe skin remained free of itch for the ensuing 4 hours. This resultshows that a monohydroxytricarboxylic ester can provide beneficialanti-itching effects, represpentative of other beneficial effects forvarious cosmetic conditions and dermatological indications.

EXAMPLE 9

Trimethyl citrate 10 g was mixed with 90 g ointment prepared from whitepetrolatum 50 parts, mineral oil 40 parts and white beeswax 10 parts.The composition thus prepared contained 10% trimethyl citrate in awater-non-washable ointment.

A male subject, age 73, topically applied the above 10% trimethylcitrate ointment on his lips. After one to two minutes, the lipsexperienced very slight sensual and plumping feelings. Such action onthe nerves of the lips shows that another monohydroxytricarboxylic estercan provide a beneficial effect, representative of other beneficialeffects for various cosmetic conditions and dermatological indications.

EXAMPLE 10

Lidocaine 5 g was dissolved in warm propylene glycol 20 ml, and thesolution thus obtained was mixed with 75 g ointment prepared from whitepetrolatum 50 parts, mineral oil 40 parts and white beeswax 10 parts.The composition thus prepared contained 5% lidocaine in awater-non-washable ointment.

A male subject, age 73, topically applied the above 5% lidocaineointment on his lips. After a few minutes, the lips felt numb and theinsensible numbing effect lasted for several hours. Such numbing oranesthetic effect was completely different from the sensual andsensational effects produced by a hydroxy-oligocarboxylic ester.

EXAMPLE 11

Tripropyl citrate 10 g was mixed with 90 g ointment prepared from whitepetrolatum 50 parts, mineral oil 40 parts and white beeswax 10 parts.The composition thus prepared contained 10% tripropyl citrate in awater-non-washable ointment.

A male subject, age 73, topically applied the above 10% tripropylcitrate ointment on his lips. After a few minutes, the lips experiencedsensual and sensational feelings which lasted for about 1.5 to 2 hours.Such action on the nerves of the lips shows that anothermonohydroxytricarboxylic ester can provide a beneficial effect,representative of other beneficial effects for various cosmeticconditions and dermatological indications.

EXAMPLE 12

Tripropyl citrate 10 g and propylene glycol 20 ml were mixed withhydrophilic ointment or oil-in-water emulsion 70 g. The composition thusprepared contained 10% tripropyl citrate in water-soluble oil-in-wateremulsion.

A male subject, age 73, having atopic eczema with severe itching skin,topically applied the above 10% tripropyl citrate cream on his right legwith itchy eczematous lesions. After a few minutes, the itch disappearedcompletely, and the skin remained free of itch for the ensuing 4 hours.This result shows that a different monohydroxytricarboxylic ester in adifferent formulation can provide beneficial anti-itching effects,represpentative of other beneficial effects for various cosmeticconditions and dermatological indications.

EXAMPLE 13

Tri-isopropyl citrate 10 g was mixed with 90 g ointment prepared fromwhite petrolatum 50 parts, mineral oil 40 parts and white beeswax 10parts. The composition thus prepared contained 10% tri-isopropyl citratein a water-non-washable ointment.

A male subject, age 74, topically applied the above 10% tri-isopropylcitrate ointment on his lips. After a few minutes, the lips experiencedsensual and sensational feelings which lasted for about an hour. Thisresult shows that a different monohydroxytricarboxylic ester can providea beneficial effect, represpentative of other beneficial effects forvarious cosmetic conditions and dermatological indications.

EXAMPLE 14

Tribenzyl citrate 10 g was mixed with 90 g ointment prepared from whitepetrolatum 50 parts, mineral oil 40 parts and white beeswax 10 parts.The composition thus prepared contained 10% tribenzyl citrate in awater-non-washable ointment.

A male subject, age 74, topically applied the above 10% tribenzylcitrate ointment on his lips. After a few minutes, the lips experiencedslight sensual and sensational feelings. This result shows that adifferent, aromatic monohydroxytricarboxylic ester can provide abeneficial effect, represpentative of other beneficial effects forvarious cosmetic conditions and dermatological indications.

EXAMPLE 15

A typical combination composition was formulated as follows.Hydrocortisone-17-valerate 0.2 g was dissolved in liquid triethylcitrate 15 g and propylene glycol 10 ml. The solution thus obtained wasmixed with 74.8 g ointment prepared from white petrolatum 50 parts,mineral oil 40 parts and white beeswax 10 parts. The composition thusprepared contained 15% triethyl citrate and 0.2%hydrocortisone-17-valerate in a water-non-washable ointment.

A male subject, age 74, topically applied the above ointment on hisitchy and eczematous skin. After a few minutes the itch disappeared, andthe composition had in addition an anti-inflammatory effect. The resultsshowed that the composition would be beneficial for topical treatment ofpruritus, eczema and other inflammatory skin diseases.

EXAMPLE 16

Another typical combination composition was formulated as follows.Menthol 1 g was dissolved in liquid tri-isopropyl citrate 10 g andpropylene glycol 10 ml. The solution thus obtained was mixed with 79 gointment prepared from white petrolatum 50 parts, mineral oil 40 partsand white beeswax 10 parts. The composition thus prepared contained 10%tri-isopropyl citrate and 1% menthol in a water-non-washable ointment.

A male subject, age 74, topically applied the above ointment on hisitchy and eczematous skin. After a few minutes the itch diminished, andthe composition had a soothing effect on the eczematous lesions. Theresults showed that the composition would be beneficial for topicaltreatment of pruritus, eczema and other inflammatory skin diseases.

EXAMPLE 17

Another typical combination composition was formulated as follows.Diphenhydramine hydrochloride 58 g (0.2 mole) was dissolved in water 100ml, and 5N NaOH 40 ml (0.2 mole) was added slowly with stifling.Diphenhydramine free base was formed as oily white precipitates. Withoutisolation of the free base, N-acetyl-L-proline 48 g (0.3 mole) andN-acetyl-D-glucosamine 44 g (0.2 mole) were added with stirring into theoily mixture, and the mixture became a clear solution. Propylene glycol100 ml and water 50 ml were added to make total volume 400 ml (444 g).This formulation contained diphenhydramine 14.5%, N-acetyl-L-proline 12%and N-acetyl-D-glucosamine 11% in a propylene glycol/water solution. Theabove formulation 22 g and tribenzyl citrate 10 g were mixed withhydrophilic ointment or oil-in-water cream 68 g. The composition thusprepared had pH 3.8 and contained 10% tri-benzyl citrate, 3%diphenhydramine, 2.6% N-acetyl-L-proline and 2.4% N-acetyl-D-glucosaminein a water-washable cream.

A male subject, age 74, topically applied the above composition on hisitchy and eczematous skin. After a few minutes, the itch disappeared.The result showed that the composition would be beneficial for topicaltreatment of pruritus, eczema and other inflammatory skin diseases.

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications within the spirit and scope of thepresent invention as defined by the appended claims.

1. A method of treating a cosmetic condition or dermatologicalindication other than an aging-related skin condition in a subject, themethod comprising topically applying to a region affected with thecondition or indication in the subject a hydroxy-oligocarboxylic esterin an amount effective to treat the condition or indication.
 2. Themethod of claim 1, wherein the hydroxy-oligocarboxylic ester is selectedfrom the group consisting of a hydroxydicarboxylic ester and ahydroxytricarboxylic ester.
 3. The method of claim 2, wherein thehydroxydicarboxylic ester and hydroxytricarboxylic ester are selectedfrom the group consisting of malate esters, citramalate esters,tartarate esters, citrate esters, isocitrate esters, homocitrate esters,homoisocitrate esters, agaricate esters, hydroxycitrate esters,hydroxyisocitrate esters, hydroxyhomocitrate esters,hydroxyhomoisocitrate esters, dihydroxycitrate esters,dihydroxyisocitrate esters, dihydroxyhomocitrate esters anddihydroxyhomoisocitrate esters.
 4. The method of claim 3, wherein themalate esters are selected from the group consisting of dimethyl malate,diethyl malate, dipropyl malate, di-isopropyl malate, diamyl malate,dioctyl malate, di-isooctyl malate and dibenzyl malate.
 5. The method ofclaim 3, wherein the tartarate esters are selected from the groupconsisting of dimethyl tartarate, diethyl tartarate, dipropyl tartarate,di-isopropyl tartarate, diamyl tartarate, dioctyl tartarate, di-isooctyltartarate and dibenzyl tartarate.
 6. The method of claim 3, wherein thecitrate esters are selected from the group consisting of trimethylcitrate, triethyl citrate, tripropyl citrate, tri-isopropyl citrate,triamyl citrate, trioctyl citrate, tri-isooctyl citrate, tribenzylcitrate and trinicotinyl citrate.
 7. The method of claim 3, wherein theisocitrate esters are selected from the group consisting of trimethylisocitrate, triethyl isocitrate, tripropyl isocitrate, tri-isopropylisocitrate, triamyl isocitrate, trioctyl isocitrate, tri-isooctylisocitrate, tribenzyl isocitrate and trinicotinyl isocitrate.
 8. Themethod of claim 1, wherein the cosmetic condition or dermatologicalindication is selected from the group consisting of acne; rosacea;blemished skin; cellulite; dermatosis; dermatitis; a skin or nailinfection; dandruff; dry skin; xerosis; eczema; herpes; ichthyosis;pseudofolliculitis barbae; pruritus; psoriasis; stretch marks; warts;oral or gum disease; irritated, inflamed, unhealthy, damaged or abnormalmucosa, skin, hair, nail, nostril, ear canal, anal or vaginal condition;uneven and rough surface of skin, nail or hair; reactive, irritating ortelangiectatic skin; for skin bleach and lightening; wound healing; anduse as an anti-oxidant for preventive care or treatment for damage,stinging or irritation of skin, hair or nails caused by sunlight,chemicals, laser treatment, free radicals, electromagnetic radiation,ionizing radiation; alpha rays, beta rays, X-rays, gamma rays or otheroxidative damages.
 9. The method of claim 8, wherein the cosmeticcondition or dermatological indication is selected from the groupconsisting of acne; rosacea; blemished skin; cellulite; dry skin;xerosis; eczema; ichthyosis; pseudofolliculitis barbae; stretch marks;warts; uneven and rough surface of skin, nail or hair; and for skinbleach and lightening.
 10. The method of claim 1, further comprisingadministering to the subject a topically active agent for a synergeticor synergistic effect with the hydroxyl-oligocarboxylic ester.
 11. Themethod of claim 10, wherein the topically active agent is selected fromthe group consisting of a hydroxyacid, ketoacid and related compounds;phenyl alpha acyloxyalkanoic acid and derivatives; N-acyl-aldosamine,N-acylamino acid and related N-acyl compounds; local analgesic, localanesthetic; anti-acne agent; anti-bacterial agent; anti-yeast agent;anti-fungal agent; anti-viral agent; anti-infective agent; anti-dandruffagent; anti-dermatitis agent; anti-eczema agent; anti-histamine agent;anti-pruritic agent; anti-emetic; anti-motion sickness agent;anti-inflammatory agent; anti-hyperkeratotic agent; antiperspirant;anti-psoriatic agent; anti-rosacea agent; anti-seborrheic agent; hairconditioner; hair treatment agent; anti-wrinkle agent; anti-anxietyagent; anti-convulsant agent; anti-depressant agent; sunblock agent;sunscreen agent; skin lightening agent; depigmenting agent; astringent;cleansing agent; corn, callus or wart removing agent; skin plumpingagent; skin volumizing agent; skin firming agent; matrixmetalloproteinase (MMP) inhibitor; topical cardiovascular agent;wound-healing agent; gum disease or oral care agent; amino acid;peptide; dipeptide; tripeptide; glutathione and its derivatives;oligopeptide; polypeptide; carbohydrate; aminocarbohydrate; vitamin;corticosteroid; tanning agent; hormone; and retinoid.
 12. The method ofclaim 11, wherein the topically active agent is selected from the groupconsisting of abacavir, acebutolol, acetaminophen, acetaminosalol,acetazolamide, acetohydroxamic acid, acetylsalicylic acid,N-acylglutathione esters, acitretin, aclovate, acrivastine, actiq,acyclovir, adalimumab, adapalene, adefovir dipivoxil, adenosine,albuterol, alfuzosin, allopurinol, alloxanthine, almotriptan,alprazolam, alprenolol, aluminum acetate, aluminum chloride, aluminumchlorohydroxide, aluminum hydroxide, amantadine, amiloride, aminacrine,p-aminobenzoic acid, aminocaproic acid, aminolevulinic acid,aminosalicylic acid, amiodarone, amitriptyline, amlodipine, amocarzine,amodiaquin, amorolfine, amoxapine, amphetamine, ampicillin, anagrelide,anastrozole, anthralin, apomorphine, aprepitant, arbutin, aripiprazole,ascorbic acid, ascorbyl palmitate, atazanavir, atenolol, atomoxetine,atropine, azathioprine, azelaic acid, azelastine, azithromycin,bacitracin, beclomethasone dipropionate, bemegride, benazepril,bendroflumethiazide, benzocaine, benzonatate, benzophenone, benzoylperoxide, benztropine, bepridil, betamethasone dipropionate,betamethasone valerate, brimonidine, brompheniramine, bupivacaine,buprenorphine, bupropion, burimamide, butenafine, butoconazole,cabergoline, caffeic acid, caffeine, calcipotriene, camphor, candesartancilexetil, cap saicin, carbamazepine, carbamide peroxide, cefditorenpivoxil, cefepime, cefpodoxime proxetil, celecoxib, cetirizine,cevimeline, chitosan, chlordiazepoxide, chlorhexidine, chloroquine,chlorothiazide, chloroxylenol, chlorpheniramine, chlorpromazine,chlorpropamide, ciclopirox, cilostazol, cimetidine, cinacalcet,ciprofloxacin, citalopram, citric acid, cladribine, clarithromycin,clemastine, clindamycin, clioquinol, clobetasol propionate, clocortolonepivalate, clomiphene, clonidine, clopidogrel, clotrimazole, clozapine,coal tar, coal tar extracts (LCD), cocaine, codeine, cromolyn,crotamiton, cyclizine, cyclobenzaprine, cycloserine, cytarabine,dacarbazine, dalfopristin, dapsone, daptomycin, daunorubicin,deferoxamine, dehydroepiandrosterone, delavirdine, desipramine,desloratadine, desmopres sin, desoximetasone, dexamethasone,dexmedetomidine, dexmethylphenidate, dexrazoxane, dextroamphetamine,diazepam, diclofenac, dicyclomine, didanosine, dihydrocodeine,dihydromorphine, diltiazem, 6,8-dimercaptooctanoic acid (dihydrolipoicacid), diphenhydramine, diphenoxylate, dipyridamole, disopyramide,dobutamine, dofetilide, dolasetron, donepezil, dopa esters, dopamide,dopamine, dorzolamide, doxepin, doxorubicin, doxycycline, doxylamine,doxypin, duloxetine, dyclonine, econazole, efalizumab, eflornithine,eletriptan, emtricitabine, enalapril, ephedrine, epinephrine, epinine,epirubicin, eptifibatide, ergotamine, erythromycin, escitalopram,esmolol, esomeprazole, estazolam, estradiol, etanercept, ethacrynicacid, ethinyl estradiol, etidocaine, etomidate, famciclovir, famotidine,felodipine, fentanyl, ferulic acid, fexofenadine, flecainide,fluconazole, flucytosine, fluocinolone acetonide, fluocinonide,5-fluorouracil, fluoxetine, fluphenazine, flurazepam, fluticasonepropionate, fluvoxamine, formoterol, furosemide, galactarolactone,galactonic acid, galactonolactone, galantamine, gatifloxacin, gefitinib,gemcitabine, gemifloxacin, glucarolactone, gluconic acid,gluconolactone, glucuronic acid, glucuronolactone, glycolic acid,griseofulvin, guaifenesin, guanethidine, N-guanylhistamine, haloperidol,haloprogin, hexylresorcinol, homatropine, homosalate, hydralazine,hydrochlorothiazide, hydrocortisone, hydrocortisone 21-acetate,hydrocortisone 17-butyrate, hydrocortisone 17-valerate, hydrogenperoxide, hydromorphone, hydroquinone, hydroquinone monoether,hydroxyzine, hyoscyamine, hypoxanthine, ibuprofen, ichthammol,idarubicin, imatinib, imipramine, imiquimod, indinavir, indomethacin,infliximab, irbesartan, irinotecan, isoetharine, isoproterenol,itraconazole, kanamycin, ketamine, ketanserin, ketoconazole, ketoprofen,ketotifen, kojic acid, labetalol, lactic acid, lactobionic acid,lamivudine, lamotrigine, lansoprazole, letrozole, leuprolide,levalbuterol, levofloxacin, lidocaine, linezolid, lobeline, loratadine,loperamide, losartan, loxapine, lysergic diethylamide, mafenide, malicacid, maltobionic acid, mandelic acid, maprotiline, mebendazole,mecamylamine, meclizine, meclocycline, memantine, menthol, meperidine,mepivacaine, mequinol, mercaptopurine, mescaline, metanephrine,metaproterenol, metaraminol, metformin, methadone, methamphetamine,methotrexate, methoxamine, methyldopa esters, methyldopamide,3,4-methylenedioxymethamphetamine, methyllactic acid, methyl nicotinate,methylphenidate, methyl salicylate, metiamide, metolazone, metoprolol,metronidazole, mexiletine, miconazole, midazolam, midodrine, miglustat,minocycline, minoxidil, mirtazapine, mitoxantrone, moexiprilat,molindone, monobenzone, morphine, moxifloxacin, moxonidine, mupirocin,nadolol, naftifine, nalbuphine, nalmefene, naloxone, naproxen,nefazodone, nelfinavir, neomycin, nevirapine, nicardipine, nicotine,nifedipine, nimodipine, nisoldipine, nitrofurantoin, nizatidine,norepinephrine, nystatin, octopamine, octreotide, octylmethoxycinnamate, octyl salicylate, ofloxacin, olanzapine, olmesartanmedoxomil, olopatadine, omeprazole, ondansetron, oxiconazole,oxotremorine, oxybenzone, oxybutynin, oxycodone, oxymetazoline, padimateO, palonosetron, pantothenic acid, pantoyl lactone, paroxetine,pemoline, penciclovir, penicillamine, penicillins, pentazocine,pentobarbital, pentostatin, pentoxifylline, pergolide, perindopril,permethrin, phencyclidine, phenelzine, pheniramine, phenmetrazine,phenobarbital, phenol, phenoxybenzamine, phentolamine, phenylephrine,phenylpropanolamine, phenytoin, physostigmine, pilocarpine,pimecrolimus, pimozide, pindolol, pioglitazone, pipamazine, piperonylbutoxide, pirenzepine, podofilox, podophyllin, povidone iodine,pramipexole, pramoxine, prazosin, prednisone, prenalterol, prilocaine,procainamide, procaine, procarbazine, promazine, promethazine,promethazine propionate, propafenone, propoxyphene, propranolol,propylthiouracil, protriptyline, pseudoephedrine, pyrethrin, pyrilamine,pyrimethamine, quetiapine, quinapril, quinethazone, quinidine,quinupristin, rabeprazole, reserpine, resorcinol, retinal, 13-cisretinoic acid, retinoic acid, retinol, retinyl acetate, retinylpalmitate, ribavirin, ribonic acid, ribonolactone, rifampin,rifapentine, rifaximin, riluzole, rimantadine, risedronic acid,risperidone, ritodrine, rivastigmine, rizatriptan, ropinirole,ropivacaine, salicylamide, salicylic acid, salmeterol, scopolamine,selegiline, selenium sulfide, serotonin, sertaconazole, sertindole,sertraline, shale tar, sibutramine, sildenafil, sotalol, streptomycin,strychnine, sulconazole, sulfacetamide, sulfabenz, sulfabenzamide,sulfabromomethazine, sulfacetamide (sodium sulfacetamide),sulfachlorpyridazine, sulfacytine, sulfadiazine, sulfadimethoxine,sulfadoxine, sulfaguanole, sulfalene, sulfamethizole, sulfamethoxazole,sulfanilamide, sulfapyrazine, sulfapyridine, sulfasalazine,sulfasomizole, sulfathiazole, sulfisoxazole, sulfur, tacrolimus,tadalafil, tamsulosin, tartaric acid, tazarotene, tegaserol,telithromycin, telmisartan, temozolomide, tenofovir disoproxil,terazosin, terbinafine, terbutaline, terconazole, terfenadine,tetracaine, tetracycline, tetrahydrozoline, thalidomide, theobromine,theophylline, thiabendazole, thioctic acid (lipoic acid), thioridazine,thiothixene, thymol, tiagabine, timolol, tinidazole, tioconazole,tirofiban, tizanidine, tobramycin, tocainide, tolazoline, tolbutamide,tolnaftate, tolterodine, tramadol, tranylcypromine, trazodone,triamcinolone acetonide, triamcinolone diacetate, triamcinolonehexacetonide, triamterene, triazolam, triclosan, triflupromazine,trimethoprim, trimipramine, tripelennamine, triprolidine, tromethamine,tropic acid, tyramine, undecylenic acid, urea, urocanic acid, ursodiol,vardenafil, venlafaxine, verapamil, vitamin E acetate, voriconazole,warfarin, wood tar, xanthine, zafirlukast, zaleplon, zinc pyrithione,ziprasidone, zolmitriptan and zolpidem.